@article{discovery10205446,
           pages = {4853--4863},
            note = {This version is the author accepted manuscript. For information on re-use, please refer to the publisher's terms and conditions.},
          number = {17},
         journal = {Cancer Research},
           title = {Chromosomal instability selects gene copy number variants
encoding core regulators of proliferation in ER+ breast cancer},
            year = {2014},
          volume = {74},
           month = {September},
       publisher = {AMER ASSOC CANCER RESEARCH},
        abstract = {Chromosomal instability (CIN) is associated with poor outcome in epithelial malignancies, including breast carcinomas. Evidence suggests that prognostic signatures in estrogen receptor-positive (ER+) breast cancer define tumors with CIN and high proliferative potential. Intriguingly, CIN induction in lower eukaryotic cells and human cells is context dependent, typically resulting in a proliferation disadvantage but conferring a fitness benefit under strong selection pressures. We hypothesized that CIN permits accelerated genomic evolution through the generation of diverse DNA copy-number events that may be selected during disease development. In support of this hypothesis, we found evidence for selection of gene amplification of core regulators of proliferation in CIN-associated cancer genomes. Stable DNA copy-number amplifications of the core regulators TPX2 and UBE2C were associated with expression of a gene module involved in proliferation. The module genes were enriched within prognostic signature gene sets for ER+ breast cancer, providing a logical connection between CIN and prognostic signature expression. Our results provide a framework to decipher the impact of intratumor heterogeneity on key cancer phenotypes, and they suggest that CIN provides a permissive landscape for selection of copy-number alterations that drive cancer proliferation.},
             url = {https://doi.org/10.1158/0008-5472.can-13-2664},
          author = {Endesfelder, David and Burrell, Rebecca A and Kanu, Nnennaya and McGranahan, Nicholas and Howell, Mike and Parker, Peter J and Downward, Julian and Swanton, Charles and Kschischo, Maik},
        keywords = {Science \& Technology, Life Sciences \& Biomedicine, Oncology, EXPRESSION PROFILES, ANEUPLOIDY, SURVIVAL, PROGNOSIS, GENOME, TOOL},
            issn = {0008-5472}
}